It is well known that the heart increases in muscle mass in response to increases in work load. In recent years, there has been considerable interest in studying the mechanisms responsible for this growth, their control and their relation to cardiac function. During the past six years, the applicant has studied the changes in biosynthesis of myocardial proteins and nucleic acids that accompany pressure-induced cardiac hypertrophy. In the present proposal, we plan to focus attention on thyroxin-induced hypertrophy. Thyroid hormone causes hypertrophy and increased accumulation of myofibrillar proteins within the heart. The speed of contraction is increased and it has been suggested that this may be the result of increased myosin ATPase activity. The mechanism whereby thyroxin induces and increase in myosin ATPase is unknown, but recent observations by the applicant and others suggest that a conformational change in the active site at or near the SH1 thiols may be involved. Support is requested to explore the several possible explanations for the effects of thyroxin or cardiac myosin. These studies of thyrotoxic myosin will include: (1) characterization of the enzymatic properties, including actin-activated ATPase activity, nucleotide and divalent metal binding, (2) microcalorimetric measurements of myosin-ligand interactions, (3) survey of light and heavy chains by peptide "mapping" for evidence of structural abnormalities, (4) isolation and characterization of peptide(s) containing the SH1 thiols, (5) exploration of the role of phosphorylation, methylation and acetylation of myosin in the change in ATPase activity, (6) measurement of the synthesis and degradation of myosin and its subunits in thyrotoxicosis and (7) correlation of changes in activity of the isolated enzyme with hemodynamic function of the heart and histochemical evidence of myofibrillar ATPase activity. Elucidation of the molecular basis for the action of thyroid hormone on myosin ATPase would constitute an important advance in our understanding of physiological adjustments in myocardial performance.